In normal tissues, cells grow and differentiate in a very controlled way. This process is controlled by a number of intracellular and extracellular signaling molecules. However, the well-controlled cellular signaling process may be disrupted by a large variety of processes, for example various genetic mutations. When disruption of cellular proliferation and differentiation pathways occurs, several diseases or proliferative disorders are initiated and generate a tumor, which can develop into cancer. There are several strategies for treating proliferative disorders, which include chemotherapy, radiotherapy, immunotherapy, or a combination of these treatments. However, certain cancers are not responsive or only partially responsive to these treatments. In other cases, such treatment strategies are not available or do not represent a feasible therapy within defined standards of patient care. Even with important improvements in cancer patient care over the years, survival rates for several types of tumors remain low. Accordingly, there is still a great need for the development of new strategies for therapy and diagnostics for proliferative disorders.
In recent years, monoclonal antibodies have been considered the most successful and important strategy for treating cancer patients. Monoclonal antibodies are known to have high target specificity and low incidence of side effects. These antibodies inhibit specific signaling pathways involved in tumor growth as well as induce immunological responses against tumor cells. Examples of antibodies successfully used for cancer treatment include, trastuzumab, which is an antibody for treating solid tumors expressing HER2, and rituximab, which is an antibody that targets CD20 for treating non-Hodgkin lymphoma. Due to cancer heterogeneity, it is highly desirable to develop antibody therapeutic agents against cancers for which there are few therapeutic options and/or against which the currently available therapeutic agents are ineffective (Scott A M et al. Nature Reviews Cancer 12, 278-287, 2012). Moreover, the combination of monoclonal antibodies targeting several pathways simultaneously, leads to additive or synergistic effects and represents a current trend in cancer therapy. (Henricks L M et al, Cancer Treat Rev. 41, 859-867, 2015).